Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Sepsis is the most common cause of death in intensive care units worldwide. The basic pathophysiologic defect in sepsis, causing functional abnormalities in many organ systems, remains elusive. Cardiovascular dysfunction often occurs in patients with sepsis and can present in two ways. After adequate volume resuscitation, patients in hyperdynamic or warm shock are peripherally vasodilated with a high cardiac output. Patients in a hypodynamic state (cold shock) present with increased vascular tone and low cardiac output (Kumar et al. (2000) Crit Care Clin. 16:251-287). Adults with sepsis often present in hyperdynamic shock, whereas pediatric patients can present with warm or cold shock (Ceneviva et al. (1998) Pediatrics 102:e19). Meningococcal sepsis can lead to hypodynamic shock in adults and children (Ceneviva et al., supra).
Despite an increase in cardiac output during the hyperdynamic phase of sepsis, studies indicate that the myocardium is dysfunctional. Both right and left ventricles can dilate, contractile function may decrease, and ventricular compliance is reduced (Kumar et al., supra). Additional work has demonstrated severe depression of ejection fraction in some patients with sepsis despite normal or elevated cardiac index (Parker et al., (1984) Ann Int Med 100:483-490). This dysfunction peaks within a few days of the onset of sepsis and resolves within 7 to 10 days in surviving patients (Kumar et al., supra).
Although myocardial dysfunction in sepsis has been the focus of many investigations, its etiology remains unclear. Given the significant link between sepsis and mortality, it is clear that a need exists for improved methodologies for the treatment and resolution of sepsis.